ES2389480T3 - Pharmaceutical compositions for the treatment of asthma - Google Patents

Abstract

A metered dose inhaler containing an aerosol suspension formulation, for inhalation, said aerosol suspension formulation for inhalation: an effective amount of demomethasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3, -heptafluoropropane as a propellant, in which the weight ratio of mometasone furoate to formoterol fumarate is from about 1 to 1 to about 50 to 1, in which the formulation contains less than 0-1% of a degradation product of mometasone furoate epoxide.

Description

Pharmaceutical compositions for the treatment of asthma

The present invention relates to aerosol suspension formulations that are free of chlorofluorocarbons (CFCs). More specifically, the present invention relates to formulations that are substantially free of CFCs and formulations that have a particular utility in medicinal applications, especially in pressurized metered dose inhalers (MDIs).

Measured dose inhalers have proven to be effective oral and nasal administration systems that have been widely used to administer steroidal and bronchodilator compounds to asthmatics, as well as to administer other compounds such as pentamidine and non-bronchodilator anti-inflammatory drugs. The rapid onset of activity of the compounds administered in this way and the absence of any significant side effects have resulted in a large number of compounds being formulated for administration by this route. Typically, the drug is administered to the patient by a propellant system that generally comprises one or more propellants that have the appropriate vapor pressure and that are suitable for oral or nasal administration. The most preferred propellant systems typically comprise CFC 11 propeller, CFC 12 propeller, CFC 114 propellant or mixtures thereof. Frequently, the vapor pressure of the propellant systems is adjusted by mixing a less volatile liquid excipient with the propellant.

However, CFC 11, CFC 12 and CFC 114 propellants belong to a class of compounds known as chlorofluorocarbons, which have been linked to the reduction of ozone in the atmosphere. It has been postulated that ozone blocks certain harmful UV rays and, therefore, a decrease in atmospheric ozone content will result in an increase in the incidence of skin cancer. In the 1970s certain measures were taken to reduce CFC emissions from aerosols. Other propellants such as hydrocarbons were used, or the product was administered in a different way. Because the use of CFC in medicinal applications is relatively low, that is, less than 1% of total CFC emissions, and due to the health benefits associated with metered dose inhalers, no measures were taken at that time. to restrict the use of CFC propellants in metered dose inhalers.

However, continued and more sophisticated ozone measurements have indicated that previous restrictions on the use of CFCs were insufficient and that additional important measures should be taken to radically reduce CFC emissions. Recommendations have been made that CFC production is practically interrupted. As a result, it may not be possible to continue using CFC thrusters in the medium and long term. Although some efforts have been made to use non-pressurized metered dose inhalers, many of these devices have not been entirely successful. Some of the operational issues related to them are: administration of uniform doses, mechanical complexity, supply of the necessary doses per aerosol container unit, compliance with rigorous regulatory regulations and difficulty of use for people because they are bulky and / or uncomfortable for use by the patient, particularly when the patient has an acute need for medication.

As a result, there is a need for pressurized aerosol formulations without CFCs, such as metered dose inhalers, which are substantially free of CFCs. Propeller systems without CFCs must meet several criteria for pressurized metered dose inhalers. They must be non-toxic, stable and non-reactive with the medication and the other main components in the valve / actuator. A propellant that has been found to be suitable is CF3CHFAF3, also known as HFA 227, HFC 227 or 1,1,1,2,3,3,3-hetafluoropropane. Hereinafter, this propellant will be referred to as HFA 227. However, certain physical properties, that is, the polarity and solubility of HFA 227, differ from the commonly used CFC propellants. Commonly used surfactants may be insoluble in HFA 227. In addition, when the medication is to be administered as a solution, the medication may not be readily soluble in this propellant. The polarity difference between HFA 227 and the CFC propellants used above may result in a different drug administration when HFA 227 replaces a CFC propellant. The medicine can float, settle or agglomerate in the CFC-free propeller even when this did not happen in the CFC propellant. Another propellant without chlorofluorocarbon of this type is hydrofluorocarbon 134a, also known as 1,1,9,2-tetrafluoroethane or HFA 134a. Hereinafter, this propellant will be called HFA 134a.

Prior art formulations containing mometasone in combination with HFA 227 in a metered dose inhaler use ethanol to suspend mometasone in a crystalline state in combination with the propellant. These formulations have improved stability over time.

The specific combinations noted above may not provide the solubility, stability, low toxicity, exact dosage, correct particle size (if suspended) and / or compatibility with commonly used metered dose inhaler valve assemblies. Therefore, there is a need for CFC-free formulations for the treatment of asthma, and procedures for producing them, which do not suffer the aforementioned drawbacks.

Summary of the invention

Accordingly, the present invention relates to a process for producing non-toxic formulations that are substantially free of CFCs that have improved stability and compatibility with the medicament and that are manufactured relatively easily.

The present invention also relates to a metered dose inhaler containing an aerosol suspension formulation for inhalation, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3heptafluoropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate, to about 50 µg mometasone furoate to about 6 µg formoterol fumarate , in which formoterol fumarate flocculates with mometasone furoate, and in which the formulation is substantially free of a carrier.

The present invention also relates to a metered dose inhaler containing an aerosol suspension formulation for inhalation, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; from about 0.05% to about 0.3% by weight of a bulking agent; and 1,1,1,2-tetrafluoroethane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate to about 50 µg mometasone furoate to about 6 µg formoterol fumarate, and in which formoterol fumarate flocculates with mometasone furoate.

The present invention also relates to a process for producing an aerosol suspension formulation for inhalation, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate: and 1,1,1,2,3,3-heptafluoropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate to about 50 µg mometasone furoate to about 6 µg formoterol fumarate, and wherein the formoterol fumarate is flocculated with mometasone furoate in said aerosol suspension formulation, and wherein the formulation is free of volumizing agent, comprising the steps of: mixing a dry powder combination of furoate micronized formoterol mometasone and furoate with a dry powdered surfactant to form a uniform mixture; filling said mixture in a metered dose inhaler cartridge; corrugating said cartridge with a measuring valve; and filling said cartridge with a propellant other than a chlorofluorocarbon. The present invention also relates to the products produced by the above procedure.

The present invention also relates to a metered dose inhaler containing an aerosol suspension formulation for inhalation, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; a dry powdered surfactant; and 1,1,1,2,3,3,3-heptafluoropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate, to about 50 µg mometasone furoate to about 6 µg formoterol fumarate , in which formoterol fumarate flocculates with mometasone furoate, in which the formulation is free of additional excipients, and in which the measured dose inhaler emits a dose having a uniform drug content after actuation of the inhaler. measured dose.

The present invention also relates to a metered dose inhaler containing an aerosol suspension formulation for inhalation, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3heptafluoropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate, to about 50 µg mometasone furoate to about 6 µg formoterol fumarate , in which formoterol fumarate flocculates with mometasone furoate, and in which the formulation contains less than 0.1% of a mometasone furoate epoxide degradation product.

The present invention also relates to a metered dose inhaler containing an aerosol suspension formulation for inhalation, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3heptafluoropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate, to about 50 µg mometasone furoate to about 6 µg formoterol fumarate , in which formoterol fumarate flocculates with mometasone furoate, in which the percentage of fine particles dispensed after actuation of the metered dose inhaler is approximately 55% to approximately 85%, and in which said Fine particles have a particle size of less than about 4.7 µm.

Brief description of the drawings

Figure 1 is the profile of the Andersen Cascade Impactor of the mometasone furoate of the average of three units of the 6/50 µg formoterol / momentase furoate combination inhaler per drive with HFA 227 and without volumizing agent. Figure 2 is the profile of the Andersen Cascade Impactor of the formoterol fumarate of the average of three units of the 6/50 µg formoterol / furoate fumarate combination inhaler per drive with HFA 227 and without volumizing agent. Figure 3 is the profile of the Andersen Cascade Impactor of the formoterol fumarate of the average of three units of the formoterol fumarate / mometasone furoate combination 6/50 µg per drive and HFA 134a with low volumizing agent. Figure 4 is the profile of the Andersen Cascade Impactor of the mometasone furoate of the average of three units of the formoterol fumarate / mometasone furoate combination 6/50 µg per drive and HFA 134a with low volumizing agent.

Detailed description of the invention

Mometasone furoate, the active component of ELOCON® lotion, cream and ointment, is an anti-inflammatory corticosteroid that has the chemical name of 17- (2-furoate) of 9,21-dichloro-11 (beta), 17-dihydroxy- 16 (alpha) methylpregna-1,4-diene-3,20-dione. It is practically insoluble in water; slightly soluble in methanol, ethanol and isopropanol; soluble in acetone and chloroform: and easily soluble in tetrahydrofuran. Its partition coefficient between octanol and water exceeds 5000. Mometasone may exist in various hydrated, crystalline and enantiomeric forms; for example, as a monohydrate. This product is available from Schering-Plow Corporation, Kenilworth, New Jersey.

Formoterol fumarate is a selective beta 2-adrenergic bronchodilator. Its chemical name is (±) -2-hydroxy-5 - [(1RS) -1-hydroxy-2 - [[(1RS) -2- (4-methoxyphenyl) -1-methylethyl] -amino] ethyl] formailide dihydrate. Formoterol fumarate is a white to yellowish crystalline powder, which has been described to be readily soluble in crystallized acetic acid, soluble in methanol, poorly soluble in ethanol and isopropanol, slightly soluble in water and practically insoluble in acetone, ethyl acetate and diethyl ether. Formoterol fumarate can exist in various hydrated, crystalline and enantiomeric forms, for example, as a monohydrate. This product is commercially available from Novartis Corporation, East Hanover, New Jersey.

The invention is particularly useful when the medicament is formoterol fumarate and mometasone furoate, or final salts, enantiomers and clathrates thereof.

Mometasone furoate and formoterol fumarate may be in a weight ratio of about 1 to 1 mometasone furoate relative to formoterol fumarate, or about 50 to 1 mometasone furoate relative to formoterol fumarate, or approximately 20 to 1 mometasone furoate for formoterol fumarate, or about 12 to 1 mometasone furoate for formoterol fumarate, or about 16 to 1 mometasone furoate for formoterol fumarate, or about 10 to 1 of mometasone furoate with respect to formoterol fumarate, or about 8 to 1 of mometasone furoate with respect to formoterol fumarate.

These proportions are approximately equivalent to a dose range of 6 µg formoterol fumarate with respect to 50 µg mometasone furoate per dose, or approximately 6 µg to 100 µg formoterol fumarate relative to mometasone furoate per dose, or approximately 8 µg to 100 µg formoterol fumarate relative to mometasone furoate per dose, or approximately 6 µg to 200 µg formoterol fumarate relative to mometasone furoate per dose, or approximately 8 µg to 200 µg formoterol fumarate relative to dose at mometasone furoate per dose, or about 12 µg to 200 µg of formoterol fumarate relative to mometasone furoate per dose, or about 12 µg to 400 µg of formoterol fumarate relative to mometasone furoate per dose.

The pharmaceutical propellant-based aerosol formulations in the art normally use a mixture of liquid chlorofluorocarbons as the propellant, although many others use a single propellant. As is known in the art, the propellant serves as a vehicle for both active ingredients and excipients. Fluorotricloromethane, dichlorodifluoromethane and dichlorotetrafluoroethane are the propellants most commonly used in aerosol formulations for administration by inhalation. Such chlorofluorocarbons (CFCs), however, have been implicated in the destruction of the ozone layer and its production is being phased out. HFA 134a and HFA 227 are said to be less harmful to ozone than many chlorofluorocarbon propellants and the use of both, individually or in combination, is considered within the scope of the present invention. However, conventional chlorofluorocarbons or mixtures thereof can also be used as propellants for the formulations of the present invention.

As one skilled in the art knows, a transporter and / or volumizing agent is an inert substance in which or on which the pharmacological active principle or principles and the excipient or excipients are dispersed if present. It has surprisingly been discovered that when the formulations of the present invention use HFA

227 as a propellant a conveyor is not necessary. Accordingly, a metered dose inhaler containing an aerosol suspension formulation for inhalation is disclosed, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3-heptafluoropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate, to about 50 µg mometasone furoate to about 6 µg formoterol fumarate , in which formoterol fumarate flocculates with mometasone furoate, and in which the formulation is substantially free of a carrier.

The processes for producing the formulations of the present invention preferably use HFA 227 or HFA 134a, or a combination thereof, in combination with mometasone furoate and formoterol fumarate, optionally, a liquid excipient and optionally a surfactant. The excipient facilitates the compatibility of the medicament with the propellant and also lowers the discharge pressure to an acceptable range, that is, approximately 2.76-5.52 x 105 Newton / meter2 absolute (40 to 80 psi), preferably, 3.45-4.83 x 105 newton / meter2 absolute (50 to 70 psi). The selected excipient must be non-reactive with the drugs, relatively non-toxic and should have a vapor pressure of less than approximately 3.45 x 105 Newton / meter2 absolute (50 psi).

As used hereafter, the term "medium chain fatty acids" refers to chains of alkyl groups ending in a -COOH group and having 6-12 carbon atoms, preferably 8-10 carbon atoms. carbon. The term "short chain fatty acids" refers to chains of alkyl groups ending in a -COOH group and having 4-8 carbon atoms. The term "alcohol" includes C1-C3 alcohols, such as methanol, ethanol and isopropanol.

Among the preferred excipients are: propylene glycol diesters of medium chain fatty acids available under the trade name Miglyol 840 (from Huls America, Inc. Piscataway, N.J.); medium chain fatty acid triglyceride esters available under the trade name Miglyol 812 (from Huts): perfluorodimethylcyclobutane available under the trade name Vertrel 245 (from E. I DuPont de Nemours and Co. Inc. Wilmington, Del.); perfluorocyclobutane available under the trade name octafluorocyclobutane (from Gainsville PCR, Fla.); polyethylene glycol, available under the trade name EG 400 (from BASF Parsippany, N.J.); menthol (from Pluess-Stauffer Internationl Stanford, Conn.); propylene glycol monolaurate, available under the trade name Lauroglycol (from Gattefosse Elmsford, N.Y.); diethylene glycol monoethyl ether, available under the trade name Transcutol (from Gattefosse); polyglycolized medium chain fatty acid glyceride, available under the trade name Labrafac Hydro WL 12t9 (from Gattefosse); alcohols, such as ethanol, methanol and isopropanol; eucalyptus oil, available (from Pluses-Stauffer International); and mixtures thereof.

Frequently, a surfactant is included in aerosol formulations for purposes such as contributing to the maintenance of a stable drug suspension and lubricating the measuring valve. The formulation of the present invention does not require a surfactant for the maintenance of easy dispersibility (such as by moderate agitation immediately before use), since the drugs form loose flocs in the propellant and show no tendency to settle or compact. In the case of HFA 227 after storage without alterations, the drug particles remain suspended in their flocculated state. Therefore, a surfactant can optionally be added to decrease the surface and interfacial tension between the medicaments and the propellant. When the medications, the propellant and the excipient are to form a suspension, a surfactant may or may not be necessary. When the medicament, the propellant and the excipient are to form a solution, a surfactant may or may not be necessary, depending in part on the solubility of the medicament and the particular excipient. The surfactant can be any suitable non-toxic compound that is not reactive with the medicament and that substantially reduces the surface tension between the medicament, the excipient and the propellant and / or acts as a valve lubricant. Among the preferred surfactants are: oleic acid available under the trade name oleic acid NF6321 (from Henkel Corp. Emery Group, Cincinnati, Ohio); cetylpyridinium chloride (from Arrow Chemical, Inc. Westwood, N.J.); soy lecithin available under the trade name Epikuron 200 (from Lucas Meyer Decatur, III); polyoxyethylene (20) sorbitan monolaurate, available under the trade name Tween 20 (from ICI Specialty Chemicals, Wilmington, Del.); polyoxyethylene (20) sorbitan monostearate, available under the trade name Tween 60 (from ICI); polyoxyethylene (20) sorbitan monoolete, available under the trade name Tween 80 (from ICI); polyethylene stearyl ether (10), available under the trade name Brij 76 (from ICI); polyoxyethylene oleyl ether (2), available under the trade name Brij 92 (from ICI); polyoxyethylene-polyoxypropylene ethylenediamine block copolymer, available under the trade name Tetronic 150 R1 (from BASF); polyoxypropylene-polyoxyethylene block copolymers, available under the trade names Pluronic L-92, Pluronic L-121 and Pluronic F 68 (from BASF); Castor oil ethoxylate, available under the trade name Alkasurf CO-40 (from Rhone-Poulenc Mississauga Ontario, Canada); and mixtures thereof.

As with other drugs that have a slight solubility in ethanol, there is a tendency for mometasone furoate to show crystal growth in ethanol-containing formulations. Formulation parameters that do not promote the growth of drug particle size are known. These parameters provide the advantage of minimizing the necessary ethanol concentrations, to reduce the potential for unpleasant taste sensations and make the compositions more suitable for use by children and others with low alcohol tolerance.

A certain minimum level of ethanol is preferred to provide a uniform and predictable administration of the drug from a metered dose dispenser. This minimum level is about 1 percent by weight of the total formulation, which results in a slightly acceptable drug administration. Increasing the amounts of ethanol generally improves the administration characteristics of the drug. However, to prevent the growth of drug crystals in the formulation, it is preferred to limit the concentration of ethanol. Experimental data indicates that the proportion of mometasone furoate weight to ethanol weight is important in preventing increases in particle size.

The active ingredients can be placed in the containers that house the formulation as follows: the container that houses the medication can be filled with medicine, ethanol and a surfactant in single or multiple stages, preferably in a single stage. Similarly, the propellant or mixture of propellants can be added to the vessel in the same or in multiple stages. The suspensions of the formulations of the present invention contain flocks of the ingredients. A floc is an aggregation of particles that form a type of crystal lattice structure that resists complete deposition. The lax structure of the crystalline lattice allows aggregates to be easily disintegrated and distributed quickly with a small amount of agitation. More specifically, when mometasone is suspended in a propellant, mometasone particles will eventually flocculate in the center of the suspension. These particles disperse rapidly by shaking or shaking the metered dose inhaler cartridge. Surprisingly, the addition of formoterol to the suspension did not alter these phenomena. When the propellant is HFA 227, formoterol fumarate and mometasone furoate form suspended flocs so that mometasone and formoterol are added together. When the propellant is HFA 134a, the presence of a bulking agent or carrier such as lactose in an amount of about 0.05% to about 0.3% by weight is preferred to increase drug administration after the inhaler is operated. . With formulations based on 134a, formoterol, mometasone and lactose have a tendency to settle at the bottom of the cartridge because HFA 134a is less dense than HFA 227; therefore, for uniform drug administration, agitation of the cartridge is preferred to reshape the suspension before actuation of the meter. Other volumizing agents that can be used in suspensions of HFA 134a include, for example, mannitol, glucose, sucrose and trehalose.

The formulations of the invention are prepared according to normal procedures in the art for other aerosol compositions. Normally, all components except the propellant are mixed and placed in aerosol containers. Then, the containers can be cooled to temperatures below the boiling point of the propellant, and the necessary quantity of the cooled propellant is added before the measuring valve is corrugated over the container. Alternatively, the containers can be equipped with a measuring valve before filling with a propeller, and the necessary amount of propellant will be introduced through the valve.

The formulations of the present invention can be filled in the aerosol containers using conventional filling equipment. Since HFA 227 and HFA 134a may not be compatible with all elastomeric compounds currently used in the present aerosol valve assemblies, it may be necessary to replace other materials, such as white rubber, or use excipients and optionally surfactants that mitigate the adverse effects of HFA 227 or 134a on the valve components. The suspensions of the present invention can preferably be prepared by pressure filling or cold filling methods known in the art.

Depending on the particular application, the container can be loaded with a predetermined amount of formulation for single or multiple dosing. Normally, the container is sized for multiple dosing and, therefore, it is very important that the formulation administered be substantially uniform for each dosage. For example, when the formulations are for bronchodilation, the container is normally loaded with a sufficient amount of the formulation for 200 drives.

Suitable suspensions can be explored in part by observing various physical properties of the formulation, that is, the particle agglomeration index, the size of the agglomerates and the flotation / sedimentation index of the particulate, and comparing them with an acceptable pattern. Such suitable solutions can be explored / evaluated by measuring the solubility of the drug over the entire recommended storage temperature range.

For metered dose inhalers, suspensions may be particularly preferred because of efficacy and stability considerations. Those skilled in the art may choose to add one or more preservatives, buffers, antioxidants, sweeteners and / or aromas or other taste masking agents, depending on the characteristics of the formulation.

The administration volumes of the available measuring valve vary from about 25 to about 100 microliters per actuation, while the amounts of drug substance needed in a dose to treat a particular condition are generally from about 10 to about 500 micrograms per valve actuation. . These two factors combined pose limitations that determine the points within the above ethanol parameters for a given formulation. The determination of these amounts is within the specialty of those skilled in the art.

In formulations of the present invention that are suitable for treating disorders of the lower respiratory system, such as asthma, at least a substantial part of the drug is present as suspended particles having respirable sizes, for example, from about 0.5 to about 10 micrometers in its largest dimension. In formulations that are suitable for treating disorders of the upper respiratory system, such as rhinitis, somewhat larger drug particles may be allowed, but the above size range remains preferred. When the active compound forms a suspension, the particle size should be relatively uniform, substantially varying all particles preferably between about 0.1-25 micrometers, preferably 0.5-10 micrometers, more preferably 1-5 micrometers. Particles larger than 25 micrometers can be maintained in the oropharyngeal cavity, while particles smaller than about 0.5 micrometers are preferably not used, since they would be more likely to be exhaled and, therefore, would not reach the patient's lungs.

In addition, within the scope of the present invention are methods of treating respiratory diseases susceptible to treatment with mometasone furoate and formoterol fumarate in effective amounts as set forth in Examples 3, 4 and 5 below. Medications may be administered once or twice a day according to the doses set forth in examples 3, 4 and 5.

Another aspect of the present invention comprises new formulations comprising a dispersion system of a well-mixed ternary mixture of the two powders of pharmacotological substance of mometasone furoate and formoterol fumarate dispersed with a third powder surfactant, such as, for example, lecithin, stearic acid, palmitic acid, magnesium stearate, magnesium palmitate, magnesium laureate and other dry powder combination surfactants suitable as is known to those skilled in the art.

The dry combination can be mixed, for example, in a T2C Turbula Mixer for about 5 minutes, or for as long as one skilled in the art knows that it achieves a uniform combination of the powders. This dispersion system is dosed individually in each inhaler can with a powder filling instrument, such as, for example, by means of an Autodose Powdemium - One Too Many System, in 15 ml cans coated with aluminum Teflon (FPT) - fluorinated ethylene copolymer) or coated with another polymer. The cans can then be corrugated with valves of 63 microliters or the like and filled with HFA-227 or HFA-134a propeller using a propellant filling equipment, such as, for example, a Pamasol Model P2008 / 012. After this, the cans filled with the suspended product are subjected to ultrasound by means of ultrasound, such as, for example, a 5210 Branson ultrasound for about 5 minutes, as one skilled in the art knows.

These particular formulations allow the manufacture of a combination IDM of two pharmacological substances that show a uniform Drug Content Uniformity (UCD) without the use of additional excipients and / or additives. The use of this type of 2-stage dry filling procedure excludes the possibility of crystal growth of the active ingredients during the filling process and ensures a uniform particle size distribution in the product filled during the beginning, half and The end of the filling procedure. This formulation and the filling procedure ensure adequate dispersion of the particles in the HFA-227 suspension medium, the absence of crystal growth, the absence of caking and a uniformity of adequate drug content after dose administration.

Certain aspects of the invention are further described in the following examples. In the examples, the term "percent" indicates weight percent unless the context clearly indicates otherwise. The following examples further describe the present invention.

The following dry powder combination samples were prepared

Example 1

Table 1. Dry Powder Combinations of Mometasone Furoate (91%), Formoterol Fumarate (9%) and Lecithin (0.1%, 0.01% and 0.02%) *

Mometasone Furoate (mg)

Formoterol fumarate (mg) Lecithin (mg) Total Mix Weight (mg) Weight per Can (mg)

616.0

61.70 0.686  678.4  13.57

621.0

62.00 0.070  683.1  13.66

621.0

61.80 0.144  682.9  13.66

*: All weights presented based on p / p in the ternary combination.

As is evident, the weight ratio of mometasone furoate to formoterol fumarate is about 10 to 1. Prepare, directly mix a dry powder combination of mometasone furoate, formoterol fumarate and lecithin in a Turbula mixer for approximately 5 minutes in the amounts identified above. After that, dose the mixture into the 15 ml cartridge using an Autodose Powdemium powder filling instrument or the like. After that, corrug with a 63 microliter valve and add the propellant to approximately 10 g / can. Then, ultrasound for 5 minutes.

Example 2

Table 2. IDM Formulation Combinations of Mometasone Furoate, Formoterol Fumarate, Lecithin and HFA-227 *

Mometasone Furoate (%)

Formoterol fumarate (%) Lecithin (%) HFA-227 (%)

0.1

 0.01 0.01 99.88

0.1

 0.01 0.001 99.89

0.1

 0.01 0.002 99.89

*: All weights presented based on p / p in the finished product.

Table 2 describes the various amounts of the active ingredients and surfactant when HFA-227 is combined in the finished metered dose inhaler cartridge.

Certain other aspects of the invention are further described in the following examples. Again, in the examples, the term "percent" indicates weight percent unless the context clearly indicates otherwise.

The following examples further describe the present invention.

Examples 3, 4 and 5 provide examples of the varying amounts of various principles of the formulations of the present invention.

Example 3

Proportion (Drug: Drug) Proportion of Formulation Prototype

Mometasone Furoate (%) Formoterol fumarate (%) Oleic acid (%) Ethanol (%) HFA-227 (%)

A (100 µg: 8 µg)

0,112  0.009 0.001 2,378 97.5

B (50 µg: 6 µg)

0.056  0.007 0 2,437 97.5

C (100 µg: 8 µg)

0,112  0.009 0.011 2,368 97.5

D (200 µg: 12 µg)

0.224  0.014 0.011 2,251 97.5

E (100 µg: 8 µg)

0,112  0.009 0 2,379 97.5

F (50 µ: 6 µ)

0.056  0.007 0.001 2,436 97.5

(G (50 µg: 6 µg)

0.056  0.007 0.011 2,426 97.5

H (50 µg: 6 µg)

0.056  0.007 0.011 1.5 98,426

I (50 µg: 6 µg)

0.056  0.007 0.011 1.75 98,176

J (50 µg: 6 µg)

0.056  0.007 0.0 1.5 98,437

K (50 µg: 6 µg)

0.056  0.007 0.0 1.75 98,187

L (200 µg: 12 µg)

0.224  0.014 0.011 1.5 98,251

M (200 µg: 12 µg)

0.224  0.014 0.011 1.75 98,001

N (200 µg: 12 µg)

0.224  0.014 0.0 1.5 98,282

O (200 µg: 12 µg)

0.224  0.014 0.0 1.75 98,012

Example 4

Proportion (Drug: Drug) Proportion of Formulation Prototype

Mometasone Furoate (%) Formoterol fumarate (%) Oleic acid (%) Ethanol (%) HFA134a (%)

A (100 µg: 8 µg)

0,112  0.009 0.001 2,378 97.5

B (50 µg: 6 µg)

0.056  0.007 0 2,437 97.5

C (100 µg: 8 µg)

0,112  0.009 0.011 2,388 97.5

D (200 µg: 12 µg)

0.224  0.014 0.011 2,251 97.5

E (100 µg: 8 µg)

0,112  0.009 0 2,379 97.5

F (50 µg: 6 µ)

0.056  0.007 0.001 2,436 97.5

G (50 µg: 6 µg)

0.058  0.007 0.011 2,426 97.5

H (50 µg: 6 µg)

0.058  0.007 0.011 1.5 98,426

I (50 µg: 6 µg)

0.056  0.007 0.011 1.75 98,176

J (50 µg: 6 µg)

0.056  0.007 0.0 1.5 98,437

K (50 µg: 6 µg)

0.056  0.007 0.0 1.75 98,187

L (200 µg: 12 µg)

0.224  0.014 0.011 1.5 98,251

MP (200 µg: 12 µg)

0.224  0.014 0.011 1.75 98,001

N (200 µg: 12 µg

0.224  0.014 0.0 1.5 98,262

O (200 µg: 12 µg)

0.224  0.014 0.0 1.75 98,012

Example 5

Proportion (Drug: Drug) Proportion of Formulation Prototype

Mometasone Furoate (%) Formoterol fumarate (%) Oleic acid (%) Ethanol (%) HFA-227 / HFA134a (50:50) (%)

A (100 µg: 8 µg)

0,112  0.009 0.001 2,378 97.5

B (50 µg: 6 µg)

0.068  0.007 0 2,437 97.5

C (100 µg: 8 µg)

0,112  0.009 0.011 2,368 97.5

D (200 µg: 12 µg)

0.224  0.014 0.011 2,251 97.5

E (100 µg: 8 µg)

0,112  0.009 0 2,379 97.5

F (50 µg: 6 µ)

0.058  0.007 0.001 2,438 97.5

G (50 µg: 6 µg)

0.058  0.007 0.011 2,426 97.5

H (50 µg: 6 µg)

0.056  0.007 0.011 1.5 98,426

I (50 µg: 6 µg)

0.056  0.007 0.011 1.75 98,176

J (50 µg: 6 µg)

0.056  0.007 0.0 1.5 98,437

K (50 µg: 6µg)

0.056  0.007 0.0 1.75 98,187

L (200 µg: 12 µg)

0.224  0.014 0.011 1.5 98,251

M (200 µg: 12 µg)

0.214  0.014 0.011 1.75 98,001

N (200 µg: 12 µg)

0.224  0.014 0.0 1.5 98,262

O (200 µg: 12 µg)

0.224  0.014 0.0 1.75 98,012

The formulations of the present invention were further analyzed using an Andersen Waterfall Impactor as described in Examples 6 and 7. The Andersen Waterfall Impactor is widely used to measure the particle size distribution of aerial particles and, more specifically, aerosols. Pharmacists The eight-phase Andersen Impactor separates the sample into nine size intervals when used with a support filter after the last impact phase. In Figures 1 to 4, this corresponds to Phase 0 of particles having a particle size of less than 10 µm to a particle size of 0.65-0.43 µm in phase 8, the final phase corresponding to the filter for particles less than 0.43 µm. The measurement of the particle size in the "throat" in the figures corresponds to the entrance hole of the Impactor. The fine particle fraction is defined as the percentage of particles that have a particle size of less than 4.7 µm. The fine particle dose is defined as the amount in µg per dose that is smaller than 4.7 µm in each drive. The µg / discharge is the total amount of drug product emitted from the measured dose inhaler after actuation. The determination of the particle size distribution of the emitted dose of the formulation using an Andersen Cascade Impactor is known to one skilled in the art.

Example 6

Andersen Waterfall Impactor data on 6/50 Formoterol / Mometasone combination inhaler g / drive-HFA 227, without volumizing agent system

Mometasone Furoate

Initial

1 month 3 months 4 months

-

4C / 40C 40C / 75% 4C / 40C 25C / 60% 40C / 75%

% Fraction of Fine Particles

36.5 16.4 25.3 9.8 30.4 18.6

Dose of Fine Particles (µg / discharge)

19.7  9.2 13.9 5.3 16.1 10.4

MMAD (micrometers)

3.7 5.0 4.1 8.3 4.2 4.6

µg / discharge (measured dose)

62.9  62.6 62.4 60.5 61.5 63.3

Formoterol fumarate

Initial

1 month 3 months 4 months

-

4C / 40C 40C / 75% 4C / 40C 25C / 60% 40C / 75%

% Fraction of Fine Particles

48.3 39.0 41.1 35.2 47.3 40.1

Dose of Fine Particles (µg / discharge)

2.6 2.2  2.4  1.9 2.6 2.2

MMAD (micrometers)

3.2 3.3  3.2  3.3 3.2 3.4

µg / discharge (measured dose)

6.6 6.3  6.6  6.3 6.5 6.5

A formulation containing 6 µg of formoterol fumarate and 50 µg of mometasone furoate using HFA 227 in the absence of a bulking agent or transporter in a metered dose inhaler was analyzed using an Andersen Cascade Impactor to analyze the amount of pharmacological principles assets and the particle size of the active ingredients that came out of the inhaler over time. As can be seen, the dose of fine particles of mometasone and formoterol over time and through temperature cycles under the specified conditions was maintained within acceptable limits (from 19.7 to 10.4 for mometasone and 2, 6 to 22 for formoterol at the point of 4 months). The dose measured for both active ingredients over time was also within acceptable limits (from 62.9 to 63.3 for mometasone and 6.6 to 6.5 for formoterol at the point of 4 months). These data correspond to the particle size distribution for mometasone and formoterol shown in Figures 1 and 2, respectively. Therefore, the data indicate an acceptable and improved pharmacological administration of the two active ingredients.

Although the fraction of fine particles of mometasone furoate seemed to decrease by almost half, this was attributed to the coarseness of the quality of mometasone furoate used. There is a correlation of the order of classification of product quality with a decrease in the size range of the corresponding drug substance suspended in the product. It was determined that the pharmacological substance containing a high proportion of large crystals that are larger than 5 to 10 micrometers produces a product with an aerodynamic particle size distribution that is outside the range of a typical effective topical pulmonary medication. The product that contains a coarser drug product also shows unacceptable particle growth with the

Time and temperature.

A finer particle size distribution of mometasone furoate improves the fraction of fine particles in the formulation that leave the inhaler after actuation of the metered dose inhaler. In fact, the quality of the mometasone used in the previous example had a percentage change in fine particle size of approximately 50% after two weeks of temperature cycles at -10 ° C and 40 ° C. However, with a similar IDM (pressurized metered dose inhaler) that only used mometasone furoate, but with a finer quality of mometasone furoate, showed a change of only about 15% or less in the fine particle size in The same cycle conditions. This results in an increase in the fraction of fine particles with respect to mometasone and, therefore, an improved drug administration of mometasone. Therefore, it has been found that when a finer particle size quality of the drug substance is used, a product is produced that has suspended drug particles that do not show particle growth over time and temperature. The aerodynamic particle size distribution is well within the range of a typical effective topical pulmonary medication, for example, more than 50% of the particles are less than 4.7 micrometers. A non-significant particle growth with time and temperature is also shown.

In the case of the oral IDM containing mometasone furoate, an example of an acceptable product profile for the power of 100 µg / drive is given below, using an Andersen Waterfall Impactor and a 1 liter inlet hole. It should be noted that the data is based on two drives of the metered dose inhaler.

Table 1

ANDERSEN CASCADA IMPACTOR PHASE

AMOUNT OF PARTICLE DEPOSITED IN PLATES

Group 1- Entry hole + Phase 0

8-22 µg

Group 2 - Phase 1 + Phase 2

12-21 µg

Group 3 - Phase 3 + Phase 4

122-140 µg

Group 4 -Phase 5-Filter

22-41 µg

The percentage of fine particles in group 1 varies from approximately 4.9% to approximately 9.8%. The percentage of fine particles in group 2 varies from approximately 7.3% to approximately 9.4%. The percentage of fine particles from phase 3 to the filter (groups 3 and 4) should preferably be in a range of about 55% to about 85%, in which the fine particles have a particle size of less than about 4 , 7 µm, preferably from 65% to 80%, or from about 80%, or from about 85%, and from about 81% to about 89% based on the data in the table above. Finally, the percentage of fine particles in group 4 varies from approximately 13.4% to approximately 18.3%.

The size of the suspended mometasone furoate drug contained in the drug product can be controlled in various ways. The pharmacological substance can be milled more efficiently before batch manufacturing the product. This could include reducing the micronization delivery rate, using a centrifugal classification to remove larger particles, and increasing the number of cycles in which the material is supplied to the micronizer, for example, double micronization. Alternatively, the drug substance can be spray dried before batch production of product, for example, by supercritical fluid technology, to create uniformly small particles of drug substance. In addition, the manufacturing process can be modified, for example, by reducing the temperature of batch manufacturing, reducing the level of alcohol used to prepare the drug concentrate, or reducing the homogenization time. Finally, other methods for controlling the particle size of the pharmacological substance that are known in the art can also be used, for example, using surfactants or other strategies for delaying particle size growth.

Example 7

Andersen Waterfall Impactor data on a 6/50 Formoterol / Mometasone combination inhaler g / drive-HFA 134a, low volumizing agent system

Mometasone Furoate

Initial

1 month 3 months 4 months

-

4C / 40C 40C / 75% 4C / 40C 25C / 80% 40C / 75%

% Fraction of Fine Particles

25.7 20.1 20.1 20.0 22.6 17.7

Dose of Fine Particles (µg / discharge)

13.6 10.6  10.1  10.0  11.4 8.8

MMAD (micrometers)

3.9 4.3  4.3  4.6  4.3 4,5

µg / discharge (measured dose)

64.1 65.0  62.2  62.6  62.1 63.7

Formoterol fumarate

Initial

1 month 3 months 4 months

4C / 40C

40C / 75%  4C / 40C 25C / 60% 40C / 75%

% Fraction of Fine Particles

42.5 38.0 41.3 40.2 43.6 40.3

Dose of Fine Particles (µg / discharge)

2.4 2.0  2.1  2.2  2.3 2.1

MMAD (micrometers)

2.9 3.1  2.9  3.2  3.0 3.1

µg / discharge (measured dose)

6.9 6.5  6.3  6.8  6.7 6.6

A formulation containing 6 µg of formoterol fumarate and 50 µg of mometasone furoate using HFA 134a with lactose as a bulking agent in a metered dose inhaler was analyzed by an Andersen Cascade Impactor to analyze the amount of pharmacological active ingredients and size particle of the 5 active ingredients that leave the inhaler over time. As can be seen, the dose of fine particles of mometasone and formoterol over time and through temperature cycles was maintained within acceptable limits (from 13.6 to 8.8 for mometasone and from 2.4 to 2 , 1 for formoterol). In addition, the measured dose actually administered was also maintained over time within acceptable limits (from 64.1 to 63.7 for mometasone, from 6.9 to 6.6 for formoterol). These data correspond to the particle size distribution 10 for the formoterol and mometasone shown in Figures 3 and 4, respectively. The fine particle fraction for both mometasone and formoterol was kept within acceptable limits. These data also indicate an improved drug administration of the two active ingredients by inhalation of measured doses. In addition, as set forth in Example 6, with a similar IDM using mometasone furoate only but with a finer quality of mometasone furoate, it showed a change of only about 15% or less in the

15 fine particle size under the same cycle conditions. This results in an increase in the fraction of fine particles with respect to mometasone and, therefore, an improved drug administration of mometasone.

Example 8

The degradation products of the formulations of the present invention were analyzed at the time of 4-20 months at 40 ° C and at a relative humidity of 75%.

IMPURITY

HFA 277, NOT VOLUMINIZED HFA 134A, WITH VOLUMINIZED SCASE

Formoterol-2566 degradation products

0.10 0.21

Total degradation of known formoterol without SCH-2566

0.10 0.09

Total degradation of unknown formoterol

0.13 0.38

Total degradation of formoterol without XSCH-2566

0.23 0.47

Compound E

0.06 0.23

Total degradation of mometasone known without Compound E

0 0

Total degradation of unknown mometasone

0.13 0.13

Total Mometasone Degradation

0.19 0.35

Total related substances

0.51 1.03

As can be seen, non-volumized formulations containing HFA 227 had substantially less degradation products as a whole compared to volumized formulations containing HFA 134a. Specifically, the formulations of HFA 227 contained less than 0.1% of a degradation product called compound E, which is an epoxide-type degradant associated with the furoate of

5 mometasone. Formulations containing mometasone furoate containing less than 0.1% of compound E meet FDA specifications for the presence of this particular compound in inhalable formulations containing mometasone furoate.

Example 9

Uniformity of the Drug Content of a 6/50 Formoterol / Mometasone combination Inhaler 10 g / drive-HFA 227, without volumizing agent system

Mometasone Furoate

initial

 1 month

-

4C / 40C 40C / 75%

Global Average µg / download

54.7  55.6 54.9

Typical deviation

11.5 9.6 6.1

Formoterol fumarate

initial

 1 month

-

4C / 40C 40C / 75%

Global Average µg / download

5.7  5.5 5.7

Relative Typical Deviation

11.6 10.4 6.8

Example 10

Uniformity of the Drug Content of a 6/50 Formoterol / Mometasone combination Inhaler g / drive-HFA 134a, low volumizing agent system

Mometasone Furoate

Initial

 1 month

-

4C / 40C 40C / 75%

Global Average µg / download

59.1  55.7 57.0

Typical deviation

17.9 10.9 19.6

Formoterol fumarate

Initial

 1 month

-

4C / 40C 40C / 75%

Global Average µg / download

6.2  5.6 6.0

Relative Typical Deviation

17.3 11.2 26.1

The Uniformity of the Drug Content (UCF) of the inhaler was measured throughout the life of a 120-dose MDI

15 to determine if there was a dose uniformity of the active ingredients throughout the life of the product. Five cartridges of each formulation (HFA 227 or HFA 134a) were analyzed and each cartridge administered 120 medication drives, and the amount of active ingredients leaving the inhaler per drive was measured in various drives, for example, numbers 11, 12, 13, 14, (start), 59, 60, 61, 62 (half) and 117, 118, 119 and 120 (end). The averages were determined for the start, middle and end drives, and

20 a global average was determined and set forth in Examples 9 and 10 above. Although the formulation of HFA 227 had a lower relative standard deviation for the amount of drug emitted throughout the lifetime of the MDI, both formulations produced acceptable results for the uniformity of the drug content over time.

In another definition of the invention, processes and products are provided as described in the following clauses:

Clause 1. A metered dose inhaler containing an aerosol suspension formulation for inhalation, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3-heptafluoropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate, to about 50 µg mometasone furoate to about 6 µg formoterol fumarate , in which formoterol fumarate flocculates with mometasone furoate, and in which the formulation is substantially free of a carrier.

Clause 2. The measured dose inhaler containing an aerosol suspension formulation for inhalation of Clause 1 which additionally comprises a surfactant.

Clause 3. The measured dose inhaler containing an aerosol suspension formulation for inhalation of Clause 1, in which mometasone furoate is present in an amount of approximately 50 µg and formoterol fumarate is present in an amount of approximately 6 µg

Clause 4. The metered dose inhaler containing an aerosol suspension formulation for inhalation of Clause 1, in which mometasone furoate is present in an amount of approximately 100 µg and formoterol fumarate is present in an amount of approximately 6 µg

Clause 5. The measured dose inhaler containing an aerosol suspension formulation for inhalation of Clause 1, in which mometasone furoate is present in an amount of approximately 50 µg and formoterol fumarate is present in an amount of approximately 8 µg

Clause 6. The measured dose inhaler containing an aerosol suspension formulation for inhalation of Clause 1, in which mometasone furoate is present in an amount of approximately 100 µg and formoterol fumarate is present in an amount of approximately 8 µg

Clause 7. The metered dose inhaler containing an aerosol suspension formulation for inhalation of Clause 1, in which mometasone furoate is present in an amount of approximately 200 µg and formoterol fumarate is present in an amount of approximately 12 µg

Clause 8. The metered dose inhaler containing an aerosol suspension formulation for inhalation of Clause 1, in which mometasone furoate is present in an amount of approximately 400 µg and formoterol fumarate is present in an amount of approximately 12 µg

Clause 9. A procedure for treating allergic and inflammatory reactions in the respiratory tract, comprising administering by inhalation an aerosol suspension formulation in accordance with Clause 1.

Clause 10. A metered dose inhaler containing an aerosol suspension formulation for inhalation, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; a volumizing agent present in an amount of about 0.05% to 0.3% by weight of the formulation; and 1,1,1,2-tetrafluoroethane; wherein the ratio of mometasone furoate to formeterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate to about 50 µg mometasone furoate to about 6 µg formoterol fumarate and in which formoterol fumarate flocculates with mometasone furoate.

Clause 11. The metered dose inhaler containing an aerosol suspension formulation for inhalation of Clause 10 which additionally comprises a surfactant.

Clause 12. The measured dose inhaler containing an aerosol suspension formulation for inhalation of the formulation of Clause 10, in which mometasone furoate is present in an amount of approximately 50 µg and formoterol fumarate is present in a amount of approximately 6 µg.

Clause 13. The measured dose inhaler containing an aerosol suspension formulation for inhalation of the formulation of Clause 10, in which mometasone furoate is present in an amount of approximately 100 µg and formoterol fumarate is present in a amount of approximately 6 µg.

Clause 14. The metered dose inhaler containing an aerosol suspension formulation for inhalation of the formulation of Clause 10, in which mometasone furoate is present in an amount of about 50 µg and formoterol fumarate is present in a amount of approximately 8 µg.

Clause 15. The metered dose inhaler containing an aerosol suspension formulation for

Inhalation of the formulation of Clause 10, wherein mometasone furoate is present in an amount of about 100 µg and formoterol fumarate is present in an amount of about 8 µg.

Clause 16. The measured dose inhaler containing an aerosol suspension formulation for inhalation of the formulation of Clause 10, in which mometasone furoate is present in an amount

10 of about 200 µg and formoterol fumarate is present in an amount of about 12 µg.

Clause 17. The metered dose inhaler containing an aerosol suspension formulation for inhalation of the formulation of Clause 10, in which mometasone furoate is present in an amount of about 400 µg and formoterol fumarate is present in a amount of about 12

15 µg

Clause 18. The metered dose inhaler containing an aerosol suspension formulation for inhalation formulation according to Clause 10, wherein the volumizing agent is selected from the group consisting of lactose, glucose, trehalose, sucrose and mannitol.

Clause 19. A procedure for the treatment of allergic and inflammatory reactions in the tract

20 which comprises administering by inhalation an aerosol suspension formulation in accordance with Clause 10.

Clause 20. A process for producing an aerosol suspension formulation by inhalation, said aerosol suspension formulation for inhalation comprising:

an effective amount of mometasone furoate; an effective amount of formoterol fumarate; Y

1,1,1,2,3,3,3, -heptafluoropropane, in which the ratio of mometasone furoate to formoterol fumarate is approximately 400 µg mometasone furoate to approximately 12 µg formoterol fumarate at about 50 µg of mometasone furoate with respect to about 6 µg of formoterol fumarate, in which formoterol fumarate flocculates with mometasone furoate in said aerosol suspension and in which the formulation is free of an agent

30 volumizer comprising the steps of:

a) mixing a combination of dry powder of micronized mometasone furoate and furoate

formoterol with a dry powdered surfactant to form a uniform mixture;

b) filling said mixture in a metered dose inhaler cartridge;

c) corrugating said cartridge with a metering valve; Y

D) filling said cartridge with a propellant other than a chlorofluorocarbon.

Clause 21. The product produced by the process of Clause 20.

Clause 22. The process according to Clause 20, wherein the dry powdered surfactant is selected from the group consisting of lecithin, stearic acid, palmitic acid, magnesium stearate, magnesium palmitate and magnesium laurate.

40 Clause 23. A metered dose inhaler containing an aerosol suspension formulation for inhalation, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; a dry powder surfactant and 1,1,1,2,3,3,3, -heptafluoropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg fumarate

45 of formoterol with respect to about 50 µg of mometasone furoate to about 6 µg of formoterol fumarate, in which formoterol fumarate flocculates with mometasone furoate, in which the formulation is free of additional excipients and in which the Measured dose inhaler emits a dose that has a uniform drug content after activation of the measured dose inhaler.

Clause 24. A metered dose inhaler containing an aerosol suspension formulation, for

Inhalation, said aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3, -heptafluoropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate, to about 50 µg mometasone furoate to about 6 µg fumarate

55 formoterol, in which formoterol fumarate flocculates with mometasone furoate, and in which the formulation

It contains less than 0.1% of a degradation product epoxid of mometasone furoate.

Clause 25. A metered dose inhaler containing an aerosol suspension formulation, for inhalation, said aerosol suspension formulation for inhalation: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3, -heptafluoropropane; in which the ratio of mometasone furoate to formoterol fumarate is about 400 µg mometasone furoate to about 12 µg formoterol fumarate to about 50 µg mometasone furoate to about 6 µg formoterol fumarate , in which formoterol fumarate flocculates with mometasone furoate, in which the percentage of fine particles dispensed after activation of the metered dose inhaler is

10 about 55% to about 85% and wherein said fine particles have a particle size of less than about 4.7 µm.

Clause 26. The measured dose inhaler containing an aerosol suspension formulation for inhalation according to Clause 25, wherein the percentage of fine particles dispensed after activation of the measured dose inhaler is approximately 65% to about 80%, and

15 wherein said fine particles have a particle size of less than about 4.7 µm.

Claims (9)

one.

 A metered dose inhaler containing an aerosol suspension formulation, for inhalation, said aerosol suspension formulation for inhalation: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3, -heptafluoropropane as a propellant, in which the weight ratio of mometasone furoate to formoterol fumarate is from about 1 to 1 to about 50 to 1, in the that the formulation contains less than 0-1% of a degradation product of mometasone furoate epoxide.

2.

 The metered dose inhaler containing an aerosol suspension formulation for inhalation of claim 1, wherein the weight ratio of mometasone furoate to formoterol fumarate is about 10 to 1.

3.

 The metered dose inhaler containing an aerosol suspension formulation for inhalation of claim 1, wherein the weight ratio of mometasone furoate to formoterol fumarate is about 20 to 1.

Four.

 The metered dose inhaler containing an aerosol suspension formulation for inhalation of claim 1, wherein the weight ratio of mometasone furoate to formoterol fumarate is about 50 to 1.

5.

 The metered dose inhaler containing an aerosol suspension formulation for inhalation according to any one of the preceding claims, further comprising a surfactant.

6.

 The metered dose inhaler containing an aerosol suspension formulation for inhalation according to any one of claims 1 to 5, wherein the formulation comprises a dry powdered surfactant and is free of additional excipients, and wherein the Measured dose inhaler emits a dose that has a uniform drug content after actuation of the measured dose inhaler

7.

 The metered dose inhaler containing an aerosol suspension formulation for inhalation according to any one of claims 1 to 6, wherein the percentage of fine particles dispensed after activation of the metered dose inhaler is approximately 55% to about 85% and wherein said fine particles have a particle size of less than about 4.7 µm.

8.

 The metered dose inhaler containing an aerosol suspension formulation for inhalation according to claim 7, wherein the percentage of fine particles dispensed after activation of the metered dose inhaler is from about 65% to about 80%, and in which said fine particles have a particle size of less than about 4.7 µm.

9.

 The aerosol suspension formulation as defined in any one of claims 1 to 8 for the treatment of allergic and inflammatory reactions in the respiratory tract, which comprises inhaling the aerosol suspension formulation.